Abstract P3053: Mitochondrial Calcium Accumulation Drives The Progression Of Non-ischemic Heart Failure: Integrated Lessons From Genetic Mouse Models

Acute mitochondrial calcium ( Ca ) uptake stimulates bioenergetics to meet increased ATP demand, but when excessive predisposes to necrotic cell death. A major unresolved controversy is whether chronic alterations in cardiomyocyte Ca homeostasis contribute to maladaptive remodeling and contractile dysfunction in non-ischemic heart disease. We hypothesized that cardiomyocyte Ca accumulation drives cardiac maladaptation in response to stressors that chronically increase workload and cytosolic Ca cycling. We subjected mice with adult, cardiomyocyte-specific manipulation of Ca uptake through the mitochondrial calcium uniporter ( deletion, -cKO; MCU overexpression, MCU-Tg) or Ca efflux through the mitochondrial sodium-calcium exchanger, NCLX (NCLX overexpression, NCLX-OE), to chronic pressure or neurohormonal overload. Fractional shortening failed to increase in -cKO mice over the first days of isoproterenol (Iso) infusion. Mortality was increased in -cKO mice over this period, and this effect was recapitulated in NCLX-OE mice infused with angiotensin II + phenylephrine (PE), although contractility did not decline in either case. Hypertrophic responses to chronic stress were attenuated in NCLX-OE but not -cKO hearts, and adenoviral NCLX expression limited mitochondrial metabolism, protein synthesis, and cell growth in neonatal rat cardiomyocytes treated with PE. These data indicate that Ca accumulation is required for cardiac hypertrophy, but MCU is not. MCU-Tg hearts decompensated towards failure with 1-2 weeks of Iso. Although these hearts exhibited increased cardiomyocyte necrosis, deletion of the mPTP regulator cyclophilin D failed to rescue contractility, suggesting that Ca overload causes cardiac failure, even independent of permeability transition. Fitting with this view, NCLX-OE attenuated the decline in contractile function that occurred with 12-week pressure overload. We conclude that despite initial adaptive effects, sustained Ca elevation drives the progression of non-ischemic heart disease triggered by a chronic increase in cardiac workload. Our findings raise concern over proposed therapeutic strategies aiming to augment Ca accumulation in heart failure.

Duke Scholars

Author Walter J. Koch Surgery, Cardiovascular and Thoracic Surgery